Innate Immune Sensor of Microbial Proteolysis Revealed

The human immune system can quickly recognize and respond to bacterial infections, but sometimes this reaction can become skewed, leading to autoimmune diseases such as rheumatoid arthritis. In this case, a person's own immune system attacks "self" proteins instead of just foreign invaders.

Interleukin 1 beta (IL-1β) is a molecule that stimulates an immune response, calling white blood cells to the site of an infection so they can engulf and clear away invading pathogens. The body first produces the molecule in a longer, inactive form that must be cleaved to be activated.

Scientists at the University of California - San Diego (La Jolla, CA,USA) investigated IL-1β function, team by analyzing the US Food and Drug Administration (FDA, Silver Springs, MD, USA) database on adverse events in rheumatoid patients who took anakinra, a drug that dampens autoimmunity by inhibiting IL-1β. They found that patients receiving anakinra were more than 300 times more likely to experience invasive, flesh-eating group A Streptococcus (GAS) infections than patients not taking the drug.

IL-1β inhibition increased susceptibility to GAS infection, but IL-1β was produced independent of canonical inflammasomes. Newly synthesized IL-1β has an amino-terminal prodomain that blocks signaling activity, which is usually proteolytically removed by caspase-1, a protease activated within the inflammasome structure. In place of host caspases, the secreted GAS cysteine protease SpeB generated mature IL-1β. During invasive infection, GAS isolates may acquire pathoadaptive mutations eliminating SpeB expression to evade detection by IL-1β. Pharmacological IL-1β inhibition alleviates this selective pressure, allowing invasive infection by non-pathoadapted GAS.

Christopher LaRock, PhD, a postdoctoral scientist and first author of the study said, “This finding may explain why some of the more invasive, flesh-eating strep strains have a genetic mutation that blocks SpeB production which helps them avoid tripping the alarm and setting off an immune response. A likely explanation for this increased risk is that with IL-1β out of the picture, as is the case with patients taking anakinra, strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system.” The study was published in the August 2016 issue of the journal Science Immunology.

Related Links:
University of California - San Diego
US Food and Drug Administration